WO1996005190A1 - 3-benzoyl benzofuran derivatives as thyroid hormone antagonists - Google Patents
3-benzoyl benzofuran derivatives as thyroid hormone antagonists Download PDFInfo
- Publication number
- WO1996005190A1 WO1996005190A1 PCT/EP1995/003214 EP9503214W WO9605190A1 WO 1996005190 A1 WO1996005190 A1 WO 1996005190A1 EP 9503214 W EP9503214 W EP 9503214W WO 9605190 A1 WO9605190 A1 WO 9605190A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carboxymethoxybenzoyl
- diiodo
- benzofuran
- butyl
- isopropyl
- Prior art date
Links
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 title description 18
- 239000005495 thyroid hormone Substances 0.000 title description 16
- 229940036555 thyroid hormone Drugs 0.000 title description 16
- 239000005557 antagonist Substances 0.000 title description 10
- TWWAVGXQPVEBKZ-UHFFFAOYSA-N 1-benzofuran-3-yl(phenyl)methanone Chemical class C=1OC2=CC=CC=C2C=1C(=O)C1=CC=CC=C1 TWWAVGXQPVEBKZ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- -1 hydroxy- Chemical class 0.000 claims abstract description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 12
- 208000035475 disorder Diseases 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 230000001105 regulatory effect Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 104
- 238000000034 method Methods 0.000 claims description 22
- 230000001419 dependent effect Effects 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 4
- CBFKXCFOWSAHNT-UHFFFAOYSA-N 2-[2,6-diiodo-4-[5-[(4-nitrobenzoyl)amino]-2-propan-2-yl-1-benzofuran-3-carbonyl]phenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(I)C(OCC(O)=O)=C(I)C=3)=C(C(C)C)OC2=CC=C1NC(=O)C1=CC=C([N+]([O-])=O)C=C1 CBFKXCFOWSAHNT-UHFFFAOYSA-N 0.000 claims description 3
- ZXLUFDIKBFVCLQ-UHFFFAOYSA-N 2-[4-[2-butyl-5-[(4-fluorobenzoyl)amino]-1-benzofuran-3-carbonyl]-2,6-diiodophenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(I)C(OCC(O)=O)=C(I)C=3)=C(CCCC)OC2=CC=C1NC(=O)C1=CC=C(F)C=C1 ZXLUFDIKBFVCLQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- CFRZMSRGTYRLPR-UHFFFAOYSA-N 2-[2,6-dibromo-4-[2-butyl-5-[(4-hydroxybenzoyl)amino]-1-benzofuran-3-carbonyl]phenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(Br)C(OCC(O)=O)=C(Br)C=3)=C(CCCC)OC2=CC=C1NC(=O)C1=CC=C(O)C=C1 CFRZMSRGTYRLPR-UHFFFAOYSA-N 0.000 claims description 2
- WLJLKTUKVIASBI-UHFFFAOYSA-N 2-[4-[2-butyl-5-[(4-hydroxybenzoyl)amino]-1-benzofuran-3-carbonyl]-2,6-diiodophenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(I)C(OCC(O)=O)=C(I)C=3)=C(CCCC)OC2=CC=C1NC(=O)C1=CC=C(O)C=C1 WLJLKTUKVIASBI-UHFFFAOYSA-N 0.000 claims description 2
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- GIQRYCUCVCSGSS-UHFFFAOYSA-N 2-[4-[2-butyl-5-[(4-methoxyphenyl)carbamoylamino]-1-benzofuran-3-carbonyl]-2,6-diiodophenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(I)C(OCC(O)=O)=C(I)C=3)=C(CCCC)OC2=CC=C1NC(=O)NC1=CC=C(OC)C=C1 GIQRYCUCVCSGSS-UHFFFAOYSA-N 0.000 claims description 2
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- WEIRLIVMVSGZJT-UHFFFAOYSA-N 2-[4-[5-[(4-hydroxybenzoyl)amino]-2-propan-2-yl-1-benzofuran-3-carbonyl]-2,6-diiodophenoxy]acetic acid Chemical compound C1=C2C(C(=O)C=3C=C(I)C(OCC(O)=O)=C(I)C=3)=C(C(C)C)OC2=CC=C1NC(=O)C1=CC=C(O)C=C1 WEIRLIVMVSGZJT-UHFFFAOYSA-N 0.000 description 1
- KAEWOCPXFSPYDH-UHFFFAOYSA-N 2-[4-[5-amino-2-(2-methylpropyl)-1-benzofuran-3-carbonyl]-2,6-diiodophenoxy]acetic acid Chemical compound CC(C)CC=1OC2=CC=C(N)C=C2C=1C(=O)C1=CC(I)=C(OCC(O)=O)C(I)=C1 KAEWOCPXFSPYDH-UHFFFAOYSA-N 0.000 description 1
- QETYJUMDMYXXFC-UHFFFAOYSA-N 2-[6-(5-amino-2-butyl-1-benzofuran-3-carbonyl)-3-ethyl-2,4-diiodophenoxy]acetic acid Chemical compound CCCCC=1OC2=CC=C(N)C=C2C=1C(=O)C1=CC(I)=C(CC)C(I)=C1OCC(O)=O QETYJUMDMYXXFC-UHFFFAOYSA-N 0.000 description 1
- XGAJABPTUOLUAE-UHFFFAOYSA-N 2-butyl-5-nitro-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=C2OC(CCCC)=CC2=C1 XGAJABPTUOLUAE-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-UHFFFAOYSA-N 2/3/6893 Natural products IC1=CC(CC(N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-UHFFFAOYSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- XKXITUMQSSTVLQ-UHFFFAOYSA-N 5-nitro-2-propan-2-yl-1-benzofuran Chemical compound [O-][N+](=O)C1=CC=C2OC(C(C)C)=CC2=C1 XKXITUMQSSTVLQ-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- OZOLVJJNEFGUEX-UHFFFAOYSA-N N-(1-benzofuran-5-yl)-1,1,1-trifluoromethanesulfonamide Chemical compound FC(S(=O)(=O)NC=1C=CC2=C(C=CO2)C=1)(F)F OZOLVJJNEFGUEX-UHFFFAOYSA-N 0.000 description 1
- MMNYIRHKECPFTL-UHFFFAOYSA-N N-(1-benzofuran-5-yl)-4-methoxybenzamide Chemical compound COC1=CC=C(C(=O)NC=2C=CC3=C(C=CO3)C=2)C=C1 MMNYIRHKECPFTL-UHFFFAOYSA-N 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102000005610 Thyroid Hormone Receptors alpha Human genes 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- QTBFPMKWQKYFLR-UHFFFAOYSA-N isobutyl chloride Chemical compound CC(C)CCl QTBFPMKWQKYFLR-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- YWQLJGMXGYUQCV-UHFFFAOYSA-N n-(1-benzofuran-2-yl)-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC2=CC=CC=C2O1 YWQLJGMXGYUQCV-UHFFFAOYSA-N 0.000 description 1
- VGCNHFYRFVWTMU-UHFFFAOYSA-N n-(1-benzofuran-2-yl)methanesulfonamide Chemical compound C1=CC=C2OC(NS(=O)(=O)C)=CC2=C1 VGCNHFYRFVWTMU-UHFFFAOYSA-N 0.000 description 1
- WZXYFENJKPVBGC-UHFFFAOYSA-N n-(1-benzofuran-5-yl)-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC=C(OC=C2)C2=C1 WZXYFENJKPVBGC-UHFFFAOYSA-N 0.000 description 1
- 108091008757 nuclear thyroid hormone receptors Proteins 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 108091008762 thyroid hormone receptors ß Proteins 0.000 description 1
- 108091008763 thyroid hormone receptors α Proteins 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This invention relates to organic compounds which function as nuclear receptor ligands and
- thyroid hormone antagonists particularly as thyroid hormone antagonists.
- thyroid hormones bind to nuclear thyroid hormone receptors.
- the complex formed by the thyroid hormone and the nuclear receptor binds to particular
- thyroid responsive elements DNA patterns, termed “thyroid responsive elements” (TRE) in the promoter region of TRE
- T-3)-regulated genes 3,5,3'- triiodothyronine (T-3)-regulated genes.
- the genes may be positively or negatively
- T3 that is to say as thyroid hormone antagonists.
- R' C M alkyl
- R 2 -NHSO 2 R 3 ; NHCOR 3 ; or -NHCONHR 3
- the compound may be selected from 2-n-Butyl-3(3,5-diiodo-4-
- the compound is preferably 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- the compounds of the present invention have an equal or better receptor binding affinity
- the compounds of the present invention may be used in the treatment of disorders which are described
- T-3 -regulated genes for example, heart arrhythymia
- a patient with a T-3-regulated gene disorder comprising administering a compound
- the disorder may be for example, heart
- arrythymia heart failure, or hyperthyroidism.
- Fig. 1 is a T3 dose response curve in TRAF o cells
- Fig. 2 illustrates the effects of 2-n-Buty 1-3(3 ,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 3 illustrates the effects of 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 4 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 5 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4- hydroxybenzamido)benzofuran on TRAF ⁇ cells;
- Fig. 6 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)-5-
- Fig. 7 illustrates the effects of 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 8 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 9 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 10 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 11 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 12 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 13 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4- hydroxyphenylureido)benzofuran on TRAF ⁇ cells;
- Fig. 14 illustrates the effects of 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4- hydroxybenzamido)benzofuran on TRAF ⁇ cells;
- Fig. 15 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-
- Fig. 16 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-
- Fig. 17 is a T3 dose response curve in TRAF ⁇ cells
- Fig. 18 illustrates the effects of 2-n-Butyl-3(3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 19 illustrates the effects of 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 20 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 21 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 22 illustrates the effects of
- Fig. 23 illustrates the effects of 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 24 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 25 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 26 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 27 illustrates the effects of 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 28 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4- methoxyphenylureido)benzofuran on TRAF ⁇ cells;
- Fig. 29 illustrates the effects of 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 30 illustrates the effects of 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-
- Fig. 31 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-
- Fig. 32 illustrates the effects of 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-
- Fig. 33 illustrates competition between 2-n-Butyl-3(3,5-diiodo-4-carboxymethoxybenzoyl)-
- Fig. 34 illustrates competition between 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-
- Fig. 35 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-
- Fig. 36 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-
- Fig. 37 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxy
- Fig. 38 illustrates the competition between 2-isopropyl-3-(3,5-diiodo-4-
- Fig. 39 illustrates the competition between 2-Isopropyl-3-(3,5-diiodo-4-
- Fig. 40 illustrates competition between 2-Isopropyl-3-(3,5-diiodo-4- carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)benzofuran and 12S I-T 3 for binding to
- Fig. 41 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-
- Fig. 42 illustrates competition between 2-Isopropyl-3-(3,5-diiodo-4- carboxymethoxybenzoyl)-5-(4-nitrobenzamido)benzofuran and 125 I-T*, for binding to ThR ⁇ l ;
- Fig. 43 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-
- Fig. 44 illustrates competition between 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)- 5-(4- hydroxyphenylureido)benzofuran and 125 I-T 3 for binding to ThR ⁇ l;
- Fig. 45 illustrates competition between 2-n-Butyl-3-(3,5-dibromo-4-
- Fig. 46 illustrates competition between 2-Isopropyl-3-(3,5-dibromo-4-
- Fig. 47 illustrates competition between 2-Isopropyl-3-(3,5-dibromo-4-
- Triethylamine (15 ml) was added and the solution was refluxed for 3h. The
- reaction mixture was diluted with ethyl acetate and washed with water and brine.
- Example 1(g) 70 mg, 0.11 mmol was treated with 4-fluorobenzoyl chloride by
- the thyroid hormone reporter cell lines (TRAF ⁇ and TRAF ⁇ ) are genetically engineered,
- thyroid hormone receptor (ThR) ⁇ and ⁇ , respectively.
- TRE thyroid hormone response element
- ALP alkaline phosphatase
- the ThR is activated resulting in transcriptional activation of the
- ALP reporter gene mediated through the TRE.
- AMPPD sodium 3-4-methoxyspiro(l,2-dioxetane-3,2'-
- AMPPD was purchased from Boule Diagnostic, Sweden.
- the cells have to
- T3 3,5,3'-triodothyronine
- the ALP reporter gene i.e. their agonistic/antagonistic activity.
- the TRAF ⁇ and ⁇ cells were seeded at a density of 2-2.5 x 10 4 cells/well in
- Coon's medium (without phenolred) (SVA, Uppsala, Sweden) + 10% FCS (Gibco-BRL)
- test for agonist activity in the absence of T3 addition :
- concentration range (example 1-3, 5): from 10 "9 to 10 s M test compound as indicated on the x-axis, vehicle only (no test compound added) appears as 10 10 M on the x-axis;
- concentration range (example 4): from 10 8 to 4xlO "5 M test compound as indicated on the
- concentration range (example 6): from 10 "7 to 4xlO "5 M test compound as indicated on the
- concentration range (example 7-10: from 5xl0 "9 to 2xlO '5 M test compound as indicated on
- concentration range (example 11-14): from 10 "7 to 3.2xlO "5 M test compound as indicated
- concentration range (example 15): from 10 "7 to 6.4xl0 5 M test compound as indicated on
- concentration range (example 1-3, 5): from 10 9 to 10 s M test compound as indicated on the
- concentration range (example 4): from 10 8 to 4xlO "5 M test compound as indicated on the x-axis in the presence of 1 nM T3, vehicle and InM T3 only (no test compound added)
- concentration range (example 6): from 10 "7 to 4xlO "5 M test compound as indicated on the
- concentration range (example 7-10): from 5xl0 "9 to 2xl0 5 M test compound as indicated on
- concentration range (example 11-14): from 10 "7 to 3.2xl0 5 M test compound as indicated
- concentration range (example 15): from 10" 7 to 6.4xlO' 5 M test compound as indicated on
- the range of affinities for the ThR ⁇ l is between 10 "5 10 M. to 10 "5 9O M.
- ThR ⁇ l are relatively small.
- ThR ⁇ and ⁇ reporter cell lines Two compounds (example 14 and 15) had a partial
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/776,924 US5854282A (en) | 1994-08-11 | 1995-08-11 | 3-benzoyl benzofuran derivatives as thyroid hormone antagonists |
DK95929866T DK0775129T3 (da) | 1994-08-11 | 1995-08-11 | 3-Benzoylbenzofuranderivater som thyroidhormonantagonister |
DE69505542T DE69505542T2 (de) | 1994-08-11 | 1995-08-11 | 3-benzoylbenzofuran-derivate als thyroidhormonantagonisten |
JP8507025A JPH10504297A (ja) | 1994-08-11 | 1995-08-11 | 甲状腺ホルモンアンタゴニストとしての3−ベンゾイルベンゾフラン誘導体 |
EP95929866A EP0775129B1 (de) | 1994-08-11 | 1995-08-11 | 3-benzoylbenzofuran-derivate als thyroidhormonantagonisten |
AU33455/95A AU694551B2 (en) | 1994-08-11 | 1995-08-11 | 3-benzoyl benzofuran derivatives as thyroid hormone antagonists |
KR1019970700890A KR970704725A (ko) | 1994-08-11 | 1995-08-11 | 수용체 리간드 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9416219.5 | 1994-08-11 | ||
GB9416219A GB9416219D0 (en) | 1994-08-11 | 1994-08-11 | Receptor ligands |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996005190A1 true WO1996005190A1 (en) | 1996-02-22 |
Family
ID=10759723
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1995/003214 WO1996005190A1 (en) | 1994-08-11 | 1995-08-11 | 3-benzoyl benzofuran derivatives as thyroid hormone antagonists |
Country Status (12)
Country | Link |
---|---|
US (1) | US5854282A (de) |
EP (1) | EP0775129B1 (de) |
JP (1) | JPH10504297A (de) |
KR (1) | KR970704725A (de) |
AT (1) | ATE172460T1 (de) |
AU (1) | AU694551B2 (de) |
CA (1) | CA2197185A1 (de) |
DE (1) | DE69505542T2 (de) |
DK (1) | DK0775129T3 (de) |
ES (1) | ES2123287T3 (de) |
GB (1) | GB9416219D0 (de) |
WO (1) | WO1996005190A1 (de) |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999058519A1 (en) * | 1998-05-12 | 1999-11-18 | American Home Products Corporation | Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
US6166069A (en) * | 1998-05-12 | 2000-12-26 | American Home Products Corporation | Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
EP1116719A2 (de) * | 2000-01-17 | 2001-07-18 | Clariant (France) S.A. | 3-(1-Hydroxy-pentylidene)-5-nitro-3H-benzofuran-2-on, ein Verfahren zu seiner Herstellung und seine Verwendung |
WO2001098256A1 (en) * | 2000-06-21 | 2001-12-27 | Karo Bio Ab | Thyroid receptor ligands, pharmaceutical compositions comprising them and their use in the treatment of disorders influenced by thyroid hormones |
FR2817864A1 (fr) * | 2000-12-11 | 2002-06-14 | Sanofi Synthelabo | Derive de methanesulfonamido-benzofurane, son procede de preparation et son utilisation comme intermediaire de synthese |
WO2003009839A1 (en) * | 2001-07-20 | 2003-02-06 | Karo Bio Ab | Benzofuranes and their use in the treatment of atrial fibrillation |
FR2864536A1 (fr) * | 2003-12-24 | 2005-07-01 | Clariant France Sa | Procede de preparation de n-alkyl-2 (hydroxy-4-benzoyl)-3 benzofurannes et intermediaires pour sa mise en oeuvre |
WO2008001959A1 (fr) | 2006-06-28 | 2008-01-03 | Sanwa Kagaku Kenkyusho Co., Ltd. | Nouveau dérivé hétérocyclique 6-5 bicyclique et utilisation médicale de celui-ci |
FR2914644A1 (fr) * | 2007-04-06 | 2008-10-10 | Finorga Soc Par Actions Simpli | Procede de preparation de 2-(n-butyl)-3-(4-hydroxybenzoyl) -5-nitrobenzofurane |
FR2914643A1 (fr) * | 2007-04-06 | 2008-10-10 | Finorga Soc Par Actions Simpli | Procede de preparation du 2-(n-butyl)-5-nitrobenzofurane |
FR2915482A1 (fr) * | 2007-04-27 | 2008-10-31 | Finorga Soc Par Actions Simpli | Procede de preparation du 2-(n-butyl)-5-nitrobenzofurane. |
US7829552B2 (en) | 2003-11-19 | 2010-11-09 | Metabasis Therapeutics, Inc. | Phosphorus-containing thyromimetics |
CN101948455A (zh) * | 2010-10-18 | 2011-01-19 | 山东邹平大展新材料有限公司 | 一种2-正丁基-3-(4-羟基苯甲酰基)-5-硝基苯并呋喃的制备方法 |
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US6317722B1 (en) * | 1998-09-18 | 2001-11-13 | Amazon.Com, Inc. | Use of electronic shopping carts to generate personal recommendations |
DE10237819A1 (de) * | 2002-08-19 | 2004-03-04 | Bayer Ag | 5-Nitrobenzofurane |
US20090028925A1 (en) * | 2005-05-26 | 2009-01-29 | Erion Mark D | Novel Phosphinic Acid-Containing Thyromimetics |
GB0611210D0 (en) * | 2006-06-07 | 2006-07-19 | Cambrex Karlskoga Ab | Process |
KR100858357B1 (ko) * | 2006-10-02 | 2008-09-11 | (주) 디지탈바이오텍 | 벤조퓨란계 유도체 화합물을 유효성분으로 함유하는인지기능 장애의 예방 및 치료용 조성물 |
GB0719180D0 (en) | 2007-10-02 | 2007-11-14 | Cambrex Karlskoga Ab | New process |
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1995
- 1995-08-11 KR KR1019970700890A patent/KR970704725A/ko active Search and Examination
- 1995-08-11 AU AU33455/95A patent/AU694551B2/en not_active Ceased
- 1995-08-11 WO PCT/EP1995/003214 patent/WO1996005190A1/en not_active Application Discontinuation
- 1995-08-11 CA CA002197185A patent/CA2197185A1/en not_active Abandoned
- 1995-08-11 AT AT95929866T patent/ATE172460T1/de not_active IP Right Cessation
- 1995-08-11 ES ES95929866T patent/ES2123287T3/es not_active Expired - Lifetime
- 1995-08-11 JP JP8507025A patent/JPH10504297A/ja active Pending
- 1995-08-11 US US08/776,924 patent/US5854282A/en not_active Expired - Fee Related
- 1995-08-11 DK DK95929866T patent/DK0775129T3/da active
- 1995-08-11 EP EP95929866A patent/EP0775129B1/de not_active Expired - Lifetime
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EP0471609A1 (de) * | 1990-08-06 | 1992-02-19 | Sanofi | Benzofuranderivate, Benzothiophene, Indole oder Indolizine, Verfahren zu ihrer Herstellung und diese enthaltende Zusammensetzungen |
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FR2803846A1 (fr) * | 2000-01-17 | 2001-07-20 | Clariant France Sa | 3-(1-hydroxy-pentylidene)-5-nitro-3h-benzofuran-2-one, son procede de preparation et son utilisation |
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Also Published As
Publication number | Publication date |
---|---|
KR970704725A (ko) | 1997-09-06 |
DK0775129T3 (da) | 1999-06-28 |
CA2197185A1 (en) | 1996-02-22 |
AU3345595A (en) | 1996-03-07 |
DE69505542D1 (de) | 1998-11-26 |
GB9416219D0 (en) | 1994-10-05 |
JPH10504297A (ja) | 1998-04-28 |
AU694551B2 (en) | 1998-07-23 |
US5854282A (en) | 1998-12-29 |
EP0775129B1 (de) | 1998-10-21 |
ES2123287T3 (es) | 1999-01-01 |
DE69505542T2 (de) | 1999-06-02 |
ATE172460T1 (de) | 1998-11-15 |
EP0775129A1 (de) | 1997-05-28 |
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